Analgetically effective tetrahydronaphthalene piperidyl derivatives



Patented Feb. is, 1945 ANALGETIOALLY EFFECTIVE TETRAHY- DRONAPHTHALENE PIPERIDYL DERIVA- TIVES Georg Scheuing and Bruno Walach,

on-the-ilhine, Germany; vested in Property Custodian No Drawing. Application December-16, 1939, Se-

rial No. 309,702. In Germany December 24,

2 Claims.

This invention relates to new analgetically eflective tetrahydronaphthalene derivatives and to processfor their production.

' According to the invention the production of the new compounds takes place in such a manner,

v that 1-oxo-2-halogen compounds of the tetrahydronaphthalene of the general formula" a nx in which x means one halogen atom have substituted in the 2-position a hydrogenated hetero- Ingelheimthe Alien cyclic nitrogen base, such as piperidine, tetrahydroisoquinoline or derivatives of these compounds according to known methods to form new compounds which have the general formula The production of the new compounds can take place for instance by substituting l-oxo- -z-halogen tetrahydronaphthalene in presence of organic solvents with the hydrogenated base, filtering oil'- irom the hydrohalide produced as byproduct, and extracting the amino ketone contained in the organic solvent and formed in the conversion by dilute acids.

For 1 mol oi fl-halogen-a-tetralon preferably at lea tilmolotnitrogenbaseareusemasatme conversion 1 mol oi hydrohalide is formed, which isboundbylmolbase. Thereactioniscarried out preferably with an excess of base, which amounts to about 2.5-3.5 mol.

. The solventswhich are to be taken into con sideration for the conversion of the initial materials are for instance benzene, acetone, ethyl "alcohol, propyl alcohol, butyl alcohol, toluene,

xylene, dioxane and higher boiling ethers' such as propyl ether and butyl ether. Water-free methyl alcohol is not a solvent applicable to the present invention. ,It is well to carry out the reaction at increased temperature, and preferably at such temperatures which correspond to the boiling temperatures of the organic solvents which are used.

Although fi-bromide-a-tetralins are generally employed as initial materials, the corresponding chlorine and iodine compounds are also suitable, although these are less easily accessible.-

The new compounds may be obtained also in such a manner, that not the hydrogenated heterocyclic nitrogen bases, but the' unhydrogenated substances are brought to conversion. Instead of piperidine, for instance pyridine may be used. But in this instance it-is necessary to hydrogenate the pyridine ring in the product obtained, which may be carried out for instance with employment of platinum as catalyst.

' The amino ketone produced in the conversion is extracted with acids from the selected organic solvent. For the extraction dilute mineral acids Example 1-1-o:co-2-N-piperidyl-1,2,3,4-tetrahy dronaphthalene 225 grams of fi-bromine-s-tetralon (1.0 mol) are .dissolved in 200 com. of benzene and this tetrahydronaphthalene of the theoretical) having the boiling point at 0.3 mm. Hg'il'iZ". The colourless hydrochloride, which is obtained tone).

according to usual methods by conversion with the stoichiometric quantity of hydrochloric acid, shows the melting point 220 0.

Example 2-6-methoaty-1 -oxo-2-N-piperidyl- 1,2,3,4-tetrahydronaphthalene 382 grams 6-methoxy-2-brom-1-oxo-1,2,3,4- tetrahydronaphthalene (1.5 mol) of the melting point 81 are dissolved in 600 com. toluene, and this solution is poured into a boiling solution of 400 grams piperidine (4.7 mol) with 750 com. toluene. After slight reaction piperidine hydrobromide separates out quickly. The solution is heated for some time on the water bath, then sucked off from the separated out piperidine hydrobromide (240 grs.=96.2% of the theory), and the amino ketone is extracted by dilute acids from the solution in toluene. From the acid solution the amino ketone is separated by dilute alkalis as thick oil taken up by an organic solvent such as benzol or ether. The residue remaining after the expulsion of the solvent is distilled or directly worked to hydrochloride or to other salts. 325 grams 6-methoxy-1-oXo-2-N-piperidyl-1,2,3,4-tetrahydronaphthalene (mol weight 259) of the boiling point 0.5 mm. 195 C. (83.8% of the theory) are obtained as thick oil, which solidifies to a crystalline mass. The colourless base can be re-crystallised from ether and then melts at 68. The hydrochloride is produced therefrom according to usual methods and shows a melting and decomposition point of 202.

Example 3-6-oa:y-1-oro-2 -'N pipericlyl-1,2,3,4 tetrahydronaphthalene 85 grams G-acetoxy-l-oxo-2-brom-1,2,3,4- tetrahydronaphthalene (=0.3 mol) are reacted in benzol with 100 grams piperidine. After the usual treatment for the production of the amino ketone salt (compare Example 1), 51 grams 6- oxy- 1-oxo-2-N-piperidyl 1,2,3,4- tetrahydronaphthalene are obtained. The hydrochloride has a melting point of 162. The yield amounts to 60% of the theory.

A similar composition is obtained by dealkylation of G-methoxyor B-ethoxy-l-oxo-Z-N-piperidyl-l,2,3,4-tetrahydronaphthalene, which can be obtained in a similar manner as the compound according to Examples 1 and 2, by means of boiling 40-45% hydrobromic acid.

Example 4-6-methoxy-1-o:c0-2-N-tetrahydroisoquinolyl-I,2,3,4-tetrahydronaphthalene 180 grams fi-methoxy-l-oxo-2-bromine-1,2,3,4- tetrahydronaphthalene (0.7 mol) are converted with 270 grams tetrahydroisoquinoline in 700 com. xylene. 172 grams 6-methoxy-1-oxo-2-N- (tetrahydroisoquinolyl)123,4 tetrahydronaphthalene are obtained with a yield of 80% of the theory of the melting point 130-132 (from ace- The hydrochloride has a melting point of 215.

Example 5 6-methoa:y -1- oxo-Z-N- (G-ethoxy-I- methyl 1,2,3,4 tetrahydroisoquinolyl)1,2,3,4- tetrahydronaphthalene '77 grams G-methoxy-1-oxo-2-bromine-1,2,3,4- tetrahydronaphthalene (0.3 mol) are converted at the boiling point with 160 grams G-ethoxy-lmethyl-1,2,3,4-tetrahydroisoquinoline in 400-500 ccm. propyl alcohol. 58 grams G-methoxy-l-oxo- 2-N-(6-ethoxy 1 methyl-1,2,3,4-tetrahydroisoquinolyl)1,2,3,4-tetrahydronaphthalene are obtained with a yield of 55% of the theory of the melting point 130. The hydrochloride has a melting point of 192.

Example 6-6-methorcy-1-oro-2-N-plperidyl- 1,2,3,4-tetrahydrc naphthalene 38 grams 6-methoxy-2-brom-1-oxo-l,2,3,4-tetrahydronaphthalene (0.15 mol) are dissolved cold with 40 grams piperidine (0.47 mol) in 150 com. acetone and the temperature of the solution is maintained at 20 by cooling. After some time 23 grams piperidine hydrobromide (93% of the theoretical) separate out. The aceton solution is worked up to amino ketone according to Example l. 23 grams 6-methoxy-1-oxo-2-N-piperidyl-1,2,3,4-tetrahydronaphthalene of the boiling point 172 at 0.2 mm. Hg are obtained. The melting point of the substance re-crystallised from ether amounts to 68. The hydrochloride has a melting point of 202. The yield amounts to 59% of the theory.

Example 76-methomy-1-o:co-2-N-pip ridgjl- 1 ,2,3,4-tetrahydronaphthalene 38 grams 6-methoxy-2-brom-1-oxo-1,2,3,4-tetrahydronaphthalene (0.15 mol) are dissolved warm in 150 com. alcohol and poured into a boiling solution of 40 grams piperidine (0.47 mol) and 150 com. alcohol. After boiling for one hour the reaction is carried out as in Example 1. 27 grams 6-methoxy -1- oxo-2-N-piperidyl-1,2,3,4-tetrahydronaphthalene of the boiling point 172 at 0.2 mm. Hg are obtained. The melting point amounts to 68. The hydrochloride has a melting point of 202. The yield amounts to 70% of the theory.

Example 8-6-methory-1-o:ro-2-N-piperidyl-1,2, 3,4-tetrahydronaphthalene 20 grams 6-methoxy-1-oxo-l,2,3,4-tetrahydronaphthalene-Z-pyridinium bromide (0.06 mol) of the melting point of 250, produced from molecular quantity 6-methoxy-l-oxo-2-brom-1,2,3,4- tctrahydronaphthalene and pyridine in xylene, are catalytically hydrogenated in methylalcoholic solution with platinum as catalyst. After a rapid absorption of 0.18 mol hydrogen, the hydrogen absorption comes to a standstill. When working up the reaction solution to amino ketone according to Example 1, 14.5 gram G-methoxy-l-oxo- 2-N-piperidyl-1,2,3,4 tetrahydronaphthalene of the boiling point172 at 0.2 mm. Hg are obtained. The melting point amounts to 68. The hydrochloride has a melting point of 202. The yield amounts to.93% of the theory.

Example 9-6-methozy-1-o:co-2-N-a-pipecolyl- 1,2,3,4-tetrahydronaphthalene 51 grams fi-methoxy 1 oxo-2-brom-1,2,3,4-

tetrahydronaphthalene (0.2 mol) are treated in a boiling dioxane with grams a-pipecoline (0.6

mol). 35 grams a-pipecoline hydrobromide (98% of the theory) separate out. When completing the working up of the reaction solution to amino ketone, 33 grams G-methoxy-1-oxo-2-N-a-pipecolyl-l,2,3,4-tetrahydronaphthalene of the boiling point 192 at 1.6 mm. Hg are obtained. The hydrochloride has a melting point of 192. The yield amounts to 60% of the theory.

Example 10-7-methyl-1-o:co-2-N-(2'4dimethyl) piperidyl-1,2,3,4-tetrahydronaphthalene Example 1 1--7-meth0:cy-1 z0-2-N (2 '4diinethyl) p peridyl-I,2,3,4-tetrahydronaphthalenle Emmpze 126-metho:z:y-1-oa:o-2-N(24'dimethyl) piperidyZ-I,2,3,4-tetrahydronaphthalene 255 grams 6-methoxy 1 oxo-2-brom-1,2,3,4-

tetrahydronaphthalene (1.0 mol) are boiled with 270 grams ZA-dimethylpiperidine (2.4 mol) in 800 com. toluene. 97% of the theory are obtained of the hydrobromide of the dimethylpiperidine. By means of tartaric acid solution, of amino ketone are isolated 28'! grams 6-methoxy-1-oxo-2- N(24'dimethyl)piperidy1 '1,2,3,4 tetrahydronaphthalene of the theory) of the boiling point 180 at 0.36 mm. Hg. The hydrochloride has a melting. point of 203 with decomposition.

Example 13-1 -oa:o-2-N (2'4 'dimethyl) piperidyl 1,2,3,4-tetrahydr0naphthalene 225 grams p-brom-atetralon (1 mol) are converted with 300 grams 2.4-dimethylpiperidine (2.65 mol) in 1000 ccm. xylene at grams hydrobromide (96% of the theory) are isolated. The amino ketone is extracted by means of citric acid solution. 103 grams 1-oxo-2-N- (2'4dimethyl) piperidyl -1,2,3,4-tetrahydronaphthalene (40% of the theory) of the boiling point 158 at 0.2 mm. Hg are obtained. The hydrochloride has a melting point of 232 with decomposition.

All temperatures are given on the centigrade scale.

We claim:

1. An analgetically eflective substance of the constitution 6-methoxy-,1-oxo-2-N-piperidyl-1,2, 3,4-tetrahydronaphthalene.

2. Analgetically effective substances, being compounds selected from the class consisting of 6- and 'Lmethoxy-1-oxo-2-N(24dimethyl) pi peridyl-1,2,3,4-tetrahydronaphthalene.

GEORG SCHEUING. BRUNO WALACH. 

